Candidate: The applicant is currently an Assistant Professor of Surgery in the Division of Surgical Oncology at the University of Cincinnati. Prior to starting this first faculty position in 8/96, he was a resident in surgery at Cornell University Medical Center and then a surgical oncology fellow at the M.D. Anderson Cancer Center. Dr. Lowy has a steadfast commitment to academic surgical oncology, and he strives to excel as both a caregiver and as a researcher. To this end, he would like to continue his basic research training in a structured, mentored environment w i t h the goal of becoming an effective, independent investigator. Environment: The research outlined in this proposal will be sponsored by Dr. Joanna Groden, an Associate Professor in the Department of Molecular Genetics, Biochemistry and Microbiology as well as an Assistant Investigator in the Howard Hughes Medical Institute. Dr. Groden is an internationally recognized expert in cancer genetics and in the study of the adenomatous polyposis coli gene. Dr. Groden and Dr. Lowy have an outstanding working relationship that has already resulted in publication of peer-reviewed manuscripts. This will be a tremendous asset in fostering Dr. Lowy's progress toward becoming an independent scientist. The University of Cincinnati is a rich and collegial intellectual environment in which to work, collaborate and study. Numerous core facilities are available within the Medical School. Research: Pancreatic cancer remains a common disease that is lethal in nearly all cases. The Wnt signaling pathway is activated in numerous malignancies by mutation of the adenomatous polyposis coli (APC) or beta-catenin genes. While APC has not previously been considered an important tumor suppressor in the pancreas, our preliminary work suggests that Wnt signaling is frequently activated in these tumors. The objective of this application is to identify target genes of Wnt signaling in pancreatic cancer. The central hypothesis is that aberrant Wnt signaling is active in a subset of pancreatic cancers and contributes to pancreatic duct carcinogenesis by transcriptional regulation of specific target genes. The central hypothesis will be tested by pursuing three specific aims: 1) To identify the genetic alterations associated with Wnt p a thway activation in pancreatic cancer in order to determine their relationship to known clinical and pathologic prognostic factors; 2) To determine whether Wnt pathway induced transcription is associated with loss of growth control in pancreatic cancer cells; 3) To identify target genes of Wnt signaling in pancreatic cancer cells. Our long-range goal is to understand how these genes contribute to pancreatic carcinogenesis with the hope that they can be modulated for therapeutic purposes.